This application is a renewal of a previous P30 entitled Center for Gene Therapy of Cystic Fibrosis and Other Genetic Diseases. As this name implies, over the past 15 years the Center's focus and membership were very broad. For this renewal the focus has been narrowed to cystic fibrosis (CF). The development of effective gene therapies for CF requires a concrete understanding of disease pathogenesis, relevant cellular targets for gene manipulation, and technologies capable of effectively delivering the CFTR gene in vivo. The creation of new CF pig and ferret models had led to rapid expansion of CF research over the past 5-year funding period. Thus, while the CF lung remains a major focus of the Center's research, other areas such as cystic fibrosis- related diabetes (CFRD) and gene delivery to the pancreas have grown significantly. For example, CFRD research at Iowa now includes the first clinical trial to study oral glucose tolerance in children 3 months to 5 years o age, with the goal of studying early insular and enteroinsular hormonal abnormalities associated with early pathogenesis of CFRD in CF ferret and pig models. The Center has productively fostered CF research through the following mechanisms. 1) The Center's Pilot and Feasibility Program, which has sponsored 59 pilots over the previous 15 years of funding, has brought numerous new Members and expertise into the Center and fostered the maturation of talented junior Associate Members to independent tenure-track faculty. 2) The establishment or expansion of several core facilities (Vector Core, Cell and Tissue Core, Comparative Pathology Core, Animal Models Core, and Clinical Core) devoted to CF research has provided Center investigators with specialized vectors, CF model systems (human, pig, ferret and mouse), and approaches that are testing important hypotheses about CF pathogenesis and developing effective therapies. These resources have also enabled the Center to serve as a resource for the distribution of viral vectors and CF pig and ferret resources to numerous outside institutions. 3) Establishment of the CF ferret and pig models (just being developed at the time of the last renewal) that develop lung, pancreatic, gallbladder and intestinal abnormalities like those observed in CF patients has greatly facilitated research by Center Members. 4) Successful maintenance of a CF Lung Tissue Acquisition Consortium of lung transplant centers has provided the well-needed airway tissue required for humanized CF model systems. 5) The Center's Enrichment Programs (consisting of a centralized website, a trainee seminar series, an external speaker seminar series, smaller informal research focus groups, and Gene Therapy Center retreats) have fostered interdisciplinary interactions and training. 6) Establishment of formal internal and external mechanisms for review of the Center, the Cores, and the Pilot and Feasibility projects has ensured a high level of excellence and the most appropriate utilization of the Center's resources. In summary, the Center has greatly strengthened existing CF research programs at the University of Iowa, while also serving as a resource for other institutions that perform gene therapy and CF research. Its effectiveness is evident from the numerous basic and applied research findings that are enhancing our understanding of CF pathogenesis and the development of new therapies.